The overall goal of this proposal is to assess the role of the essential element selenium in colorectal cancer incidence in a large cohort of women. Both human and animal studies suggest that intake of selenium is associated with reduced risk of colorectal cancer but most epidemiologic studies have been small and few have addressed risk in women. Important functions of selenium, e.g., antioxidative or anti-inflammatory properties, are mediated through selenoenzymes, which incorporate selenium into their active center. Data and biological specimens for this study are from the Women's Health Initiative Observational Study, a prospective cohort of almost 94,000 postmenopausal women, who will have been followed for an average of 8.5 years. We propose to (1) test whether high levels of serum selenium are associated with a subsequently lower risk of colorectal cancer, (2) test whether genetic variation in six specific selenoenzymes is associated with colorectal cancer risk, (3) examine the functional effect of genetic variants in selenoenzymes using laboratory assays in lymphoblastoid cell lines, and (4) investigate whether genetic variation in selenoenzymes modify the association between serum selenium and colorectal cancer. Our study will be conducted as a nested case-control study, including 925 incident colorectal cancer cases and 1,338 matched controls. Genetic variants in selenoenzymes have already been identified through our recently completed research that directly sequenced the selenoenzyme genes and identified a number of potentially important genotypes and haplotypes. We have sufficient power (88%) to detect an odds ratio (OR) for colorectal cancer of 0.7 or lower, comparing the highest with the lowest quartile of serum selenium values. For genotypes with a minor allelic frequency of 5% we have sufficient power (87%) to detect an OR of 1.5 or greater. Our interdisciplinary team will also conduct functional assays of polymorphisms to help validate the epidemiologic findings in biological systems. Results of this collaborative study will improve our understanding of the role of selenium in colorectal cancer development and of the molecular mechanisms that underlie selenium effects. This information will be particularly relevant to possible preventive effects in women, a group that has not been well studied thus far. Given the public health importance of colorectal cancer and the increasing use of selenium supplements in the United States, there is a need for the type of investigation that we are proposing.